1. Field of the Invention
The present invention relates to a series of indole derivatives. More specifically, the present invention relates to a series of substituted 3-aminoindole carboxylic acid derivatives and their bioprecursors. The compounds of this invention include prodrugs, analogs and/or bioprecursors of the active parent compounds. The parent compounds are capable of modulating T helper (Th) cells, thus controlling the transcription of interleukin-4 (IL-4) message, IL-4 release or IL-4 production, and therefore, exhibit a wide variety of therapeutic utility.
2. Description of the State of the Art
It is generally known that lymphocytes, which are produced in the bone marrow, are a class of cells that control the immune system. It is also known in the art that a class of lymphocytes known as T cells, which are educated in the thymus, are further subcategorized into helper T cells, which enhance or activate the responses of other white blood cells, such as macrophages or B cells, by secreting a variety of local mediators, lymphokines, interleukins and/or cytokines. Within this class of T cells, there are two T cell subsets, normally referred to as Th1 and Th2 cells which are distinguished by the array of cytokine genes, each cell type expresses and appears to be involved in different types of immune responses.
If uncontrolled, Th1 cells are implicated in the pathogenesis of autoimmune diseases such as type-1 diabetes, rheumatoid arthritis and multiple sclerosis (MS). Also it is known that Th2 cells are important in the eradication of helminthes and other extracellular parasites and are involved in allergic and atopic reactions. Cytokines produced by Th2 cells can induce airway hyperreactivity as well as production of IgE. Th2 cells express cytokines IL-4, IL-5 and IL-13 and can activate mast cells and eosinophils. Th2 cells stimulate B cells to proliferate and secrete antibodies effectively (humoral immunity).
Interleukin-4 is a pleiotropic type I cytokine produced by Th2 cells, basophils and mast cells, in response to receptor-mediated activation events. IL-4 is also produced by a specialized subset of T cells, some of which express NK1.1 and appear to be specific for CD-1 (NK T cells), Yoshimoto, T., et al., Science (1995) 270:1845–1847. T cells have been reported to produce IL-4, and mice lacking these cells fail to develop IL-4-dependent airway hypersensitivity upon immunization with ovalbumin in alum. Eosinophils have also been reported to be capable of producing IL-4.
IL-4 plays a central role in regulating the differentiation of antigen-stimulated naive T cells. IL-4 causes such cells to develop into cells capable of producing IL-4 and a series of other cytokines including IL-5, IL-10 and IL-13 (i.e. Th2-like cells). IL-4 powerfully suppresses the appearance of IFN-γ-producing CD4+T cells, e.g., TH1 cells. A second function of major physiologic importance is IL-4's control of the specificity of immunoglobulin class switching. IL-4 determines that human B cells switch to the expression of IgE and IgG4 and mouse B cells to IgE and IgG1. In IL-4 and IL-4 receptor knockout mice, as well as in mice that lack a principal substrate of the IL-4 receptor Stat-6, IgE production is diminished by a factor of 100-fold or more. IL-4 receptor knockout mice and Stat-6 knockout mice are also deficient in the development of IL-4-producing T cells in mice infected with the helminthic parasite Nippostrongylus brasiliensis. These physiologic functions of IL-4 give it a preeminent role in the regulation of allergic conditions; it also plays a major role in the development of protective immune responses to helminths and other extracellular parasites. In experimental and clinical situations, IL-4 appears to be capable of ameliorating the effects of tissue-damaging autoimmunity.
Thus, it is an object of this invention to provide a series of compounds that are useful in treating a wide variety of disease states caused by the imbalance of Th1/Th2 cells. Such disease states include, but not limited to, allergy, asthma, rhinitis, dermatitis B-cell lymphomas, tumors and diseases associated with bacterial, rhinovirus or respiratory syncytial virus (RSV) infections.
It is also an object of this invention to provide compounds that are capable of modulating T helper (Th) cells, Th1/Th2, thereby diminishing the number of Th2 cells in reference to the Th1 cells.
It is further an object of this invention to provide compounds that are capable of inhibiting the transcription of interleukin-4 (IL-4) message, IL-4 release or IL-4 production.
Finally, it is an object of this invention to provide compounds, which are indole derivatives that satisfy all of the objects, described hereinabove.
Other objects and further scope of the applicability of the present invention will become apparent from the detailed description to follow.
All of the references described herein are incorporated herein by reference in their entirety.